2-(aminoalkyl)-1-phenylisoindolines

ABSTRACT

NOVEL 1 - PHENYL - 2 - AMINOALKYLIDOINDOLINE DERIVATIVES HAVE BEEN PREPARED AND SHOWN TO EXHIBIT USEFUL ANOREXIGENIC PROPERTIES.

United States Patent US. Cl. 260-326.1 26 Claims ABSTRACT OF THEDISCLOSURE Novel 1 phenyl 2 aminoalkylisoindoline derivatives have beenprepared and shown to exhibit useful anorexigenie properties.

This application is a continuation-in-part of application Ser. No.487,619, filed Sept. 15, 1965 and now abandoned.

BRIEF SUMMARY OF THE INVENTION This invention relates to novelisoindoline derivatives and to novel intermediates useful in thepreparation thereof. More particularly, the invention relates tol-phenyl- 2-aminoalkylisoindoline derivatives of the formula:

wherein B represents o-phenylene or o-phenylene in which one or more ofthe hydrogen atoms have been replaced by a halogen atom, i.e., chlorine,bromine or fluorine, lower alkyl, lower alkoxy, hydroxy, amino, ortrifluoromethyl; Ph represents phenyl or phenyl in which one or more ofthe hydrogen atoms have been replaced by a halogen atom, i.e., chlorine,bromine or fluorine, lower alkyl, lower alkoxy, hydroxy, amino, ortrifluoromethyl; A represents a straight or branched chain alkylenegroup containing from 2 to 12 carbon atoms in the chain and suchalkylene groups in which part or all of the carbon atoms are in the formof a carbocycle of 3 to 7 carbon atoms; and R represents hydrogen orlower alkyl and pharmacetically acceptable acid addition salts thereof.

DETAILED DESCRIPTION In one aspect of this invention, the novelcompounds of Formula I above are prepared by treating a diester of theformula:

F CHX B (II) wherein X is halogen, preferably chlorine, iodine orbromine, or other similar leaving group such as mesyl or tosyl; and B,R, and Ph have the same significance as hereinabove with analkylenediamine of the formula:

NH --ANH case where either or both of the reactants are liquid under.

3,558,649 Patented Jan. 26, 1971 "ice the preparation of the novelcompounds of Formula I above, there can be named, for example,a,w-diaminoalkanes such as 1,2-diaminoethane, l,3-diaminopropane,1,4-diarninobutane, 1,10-diaminodecane, 1,1l-diaminoundecane,1,12-diaminododecane, etc, or amines such asl,2-diamino-Z-methylpropane, 1,3 diamino-Z-methylpropane,1,3-diaminobutane, 2,3-diaminobutane, 1,2-diaminobutane,2,5-diaminohexane, 1,2-diaminocyclohexane, 1,3- diaminocyclohexane,l,4-diaminocyclohexane, and the like. Ethylenediamine is especiallypreferred.

The reaction with diamine is conveniently carried out by adding thediester of Formula II to the diamine at room temperature. Preferably,there is employed a large molar excess of diamine. The reaction can alsobe carried out at temperatures above or below room temperature, althoughfor practical reasons, it is preferred to operate at a temperaturebetween about 0 C. and C. The reaction is suitably carried out in thepresence of an inert organic solvent, such as, for example, benzene,methylene chloride, ether, tetrahydrofuran, and the like; or, in the theconditions employed in the reaction, the reaction is convenientlycarried out in the absence of a solvent.

The diesters of Formula II employed as starting materials in thereaction are readily obtainable from the corresponding diols of theformula:

R (IJHOH CHOH (IV) wherein R, B, and Ph have the same meaning ashereinabove by the usual techniques for esterification, e.g., treatingthe diol with one of the ordinary esterifying agents such as a haloacid, acyl halides such as phosphorous halide, thionyl halide, tosylhalide, etc. The 2-hydroxymethylbenzhydrol starting material is a knowncompound which is readily prepared from the benzoylbenzoic acid byreduction with lithium aluminum hydride. Other diols of Formula N whichare per se novel can be readily prepared by analogous proceduresstarting with the appropriately substituted benzoylbenzoic acid.Suitable diols of Formula 1V prepared in this manner are, for example,S-chloro 2 hydroxymethylbenzhydrol, 4'-chloro-2-hydroxymethylbenzhydro,4' fluoro-2-hydroxymethylbenzhydrol,4'-methoxy-2-hydroxymethylbenzhydrol,2',5-dichloro-Z-l1ydroxymethylbenzhydrol, 2-(1 hydroxyethyl)-benzhydrol, 4,5-dichloro 2 hydroxymethylbenzhydrol, 2,4'-dichloro 2hydroxymethylbenzhydrol, 4-methyl- 2 hydroxymethylbenzhydrol, 3'trifluoromethyl-Z-hydroxymethylbenzhydrol, 4-trifluoromethyl 2hydroxymethylbenzhydrol, S-methoxy 2 hydroxymethylbenzhydrol, etc.

In another aspect of this invention, the novel isoindoline derivativesof Formula I are prepared by condensing a diester of Formula II with analkanolamine of the formula:

wherein A has the same meaning as hereinabove wherein A, B, R and Phhave the same meaning as hereinabove which can, in turn, be converted tothe novel end products of Formula I by esterifying to form a compound ofthe formula:

R as B\ N wherein A, B, R and Ph have the same meaning as hereinaboveand X has the same meaning as above and is preferably bromine, iodine orchlorine followed by amination.

The 2-hydroxyalkylisoindoline derivatives of Formula VI are prepared bytreating the appropriate diester of Formula II with an aminoalkanol. Thereaction is suitably carried out in the presence of an inert organicsolvent at about room temperatur e. Higher or lower temperatures such astemperatures bet een about C. and about 100 C. can also be employed.Suitable solvents for the reaction are the inert organic solvents suchas benzene, ethers, ethyl acetate, methylene chloride, and the like.

I-Ialogenation of the 2-hydroxyalkylisoindolines of Formula V1 isreadily accomplished by any of the usual techniques for halogenation,e.g., by reacting with hydrohalic acids, such as hydro'bromic acid.Alternatively, the 2-haloalkylis0indoline derivatives of Formula VII canbe obtained directly by reacting a haloalkylamine of the formula:

wherein A and X have the same meaning as hereinabove with theappropriate diester of Formula II.

The reaction is conveniently carried out in the presence of an inertorganic solvent at about room temperature.

Arnination of the intermediates of Formula VII can be readilyaccomplished by adding the appropriate ester intermediate of Formula VIIto a solution of ammonia in an organic solvent. Any organic solventwhich is inert under the conditions employed in the reaction can beutilized. Suitable solvents are, for example, tetrahydrofuran,dimethylformamide, dichloromethane, and hydrocarbon solvents, such asbenzene, etc. The reaction is readily carried out at a temperature rangebetween about -35 C. and about 200 C. Where the higher temperatures,e.g., temperatures above room temperature, are used, correspondingpressures must, of course, be employed, and the reaction is carried outin a sealed vessel.

In a particularly preferred embodiment, this invention comprisescompounds within the group defined by Formula I which are specificallyrepresented by the formula:

wherein R is hydrogen or lower alkyl; R and R are each individuallyselected from the group consisting of hydrogen, halogen or lower alkoxy;and n is an integer from 2 to 4.

The preferred intermediates of Formulae VI and VII are thosecorresponding to the end products of Formula Ia.

Suitable salts of the compounds of Formula I are prepared from nontoxicorganic and inorganic acids. Suitable organic acids are, for example,maleic acid, fumaric acid,

4 ascorbic acid, tartaric acid, salicylic acid, succinic acid, citricacid, and the like. Suitable norganic acids are, for example, thehydrohalic acids, i.e., hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, phosphoric acid, etc. The acid addition salts arereadily prepared by the usual techniques for the preparation of acidaddition salts which are readily apparent to those skilled in the art.

The novel end products of Formula -I are obtained as stereoisomers. Itis intended to include in this invention all of the stereoismeric formsof the compounds of Formula I whether they are obtained as racemicmixtures or as the separated optically active antipodes.

The novel compounds of this invention, i.e., the compounds of Formula I,are useful as anorexigenic agents. These compounds have also exhibitedmarked activity in the inhibition of ptoses induced by tetrabenazine inexperimental animals. More particularly, the novel compounds of thisinvention are therapeutically useful as appetite suppressants in thetreatment of overweight subjects.

The novel isoindoline derivatives of this invention can be administeredvia an oral or parenteral route. The preferred route of administration,however, is orally. The dosage amount and formulation can be varieddepending upon the individual response to treatment and the period andinterval during which administration is carried out. The novel compoundsof this invention can be administered either alone or in combinationwith a pharmaceutically acceptable carrier. They can be formulated intoa wide variety of dosage forms using either the bases or theirpharmaceutically acceptable acid addition salts. For purposes of oraladministration, they may be combined with various pharmaceuticallyacceptable inert carriers in the form of tablets, capsules, lozenges,troches, elixirs, syrups, and the like. Suitable carriers include soliddiluents or fillers, liquid media and various nontoxic organic solventsas, for example, sodium citrate, calcium carbonate, starch, gelatin,magnesium stearate, talc, polyethylene glycols, water, glycerine and thelike.

The invention will be more fully understood from the examples whichfollow. These examples are illustrative of the invention and are not tobe construed as limitative thereof. All melting points are in degreescentigrade.

EXAMPLE 1 Preparation of 2-(Z-aminoethyl)-1-phenylisoindoline and2-(2-aminoethyl) 1 (p-chlorophenyl)isoindoline and salts The compoundsof this invention were prepared ac cording to the following generalprocedure: A soultion of an appropriate 2-hydroxymethylbenzhydrol wasdissolved in an excess of thionyl chloride. The solution was kept on asteam bath for about 30 minutes after which time the excess of thionylchloride was removed in vacuo and the residue was distilled at 0.1 mm.and at a bath temperature ranging from about to 150". A colorless oilwas obtained which was dissolved in an inert solvent (benzene, methylenechloride, ether, tetrahydrofuran, etc.) and added in small portions to astirred excess of the corresponding diamine. The mixture was kept on asteam bath for about 30 minutes after which time the solvent as well asthe excess of the diamine were removed in vacuo. The residue wasdissolved in ether or any water immiscible organic solvent and thesolution was washed with Water, dried with sodium sulfate and evaporatedon a steam bath. The residue was distilled at 0.1 mm. and bathtemperatures ranging from 100l70 to give the 1-phenyl-2-aminoalkylisoindoline end products as colorless oils. These compoundseither crystallized on standing or were characterized in the form oftheir crystalline salts. In this way there were prepared the following:2-(2-aminoethyl)- l-phenylisoindoline, white prisms, M.P. 53;2-(2-aminoethyl)-1-phenylisoindoline dihydrochloride, white needles,M.P. 215-220" (dec.); 2-(2-aminoethyl)-1-(p-chlorophenyl)isoindoline,colorless oil, B.P. 0.1 mm. about (bath temperature); 2-(2-aminoethyl) 1(p-chlorophenyl)isoindoline monohydrochloride, white needles, M.P.218-221".

EXAMPLE 2 Preparation of 2-(2aminoethyl)-1-phenylisoindoline and varioussalts A solution of 127 g. (0.59 mole) of 2-hydroxymethylbenzhydrol wasdissolved in 900 ml. of benzene, 80 g. of anhydrous magnesium sulfatewas added and the mixture was cooled in an ice bath. Hydrogen bromidewas bubbled into the stirred solution until saturation which took aboutminutes. During this time the temperature of the solution was kept at15-18. The ice bath was removed and the temperature was allowed to riseto in the course of 1 hour. The mixture was heated for another hour at-45 on a steam bath. During the whole time hydrogen bromide was passedinto the solution to keep it saturated. The mixture was filtered and thesolution was concentrated in vacuo to give a red oil which was dissolvedin 200 ml. of benzene and added to 342 g. (5.7 mole) of ethylenediaminein the course of 15 minutes. during the addition the mixture was stirredand cooled to maintain a temperature of ca. 40. The mixture was stirredat 25 for 70 minutes. Two layers were obtained and separated. Thebenzene layer was washed with water and concentrated in vacuo. Theresidual oil was dissolved in 250 ml. of ether. This solution wasextracted twice with 300 ml. of cold 1 N hydrochloric acid. The acidicaqueous phase was made alkaline with aqueous sodium hydroxide andextracted with 350 ml. of ether. The ethereal solution was washed with25 0 ml. of water, dried and concentrated. The residue was an amber oilwhich crystallized on scratching. This material melted up to ca. and wasused for the preparation of the salts described below.

(a) Dihydrochloride-The 2 (2 aminoethyl)-1- phenylisoindoline obtainedas above was dissolved in methanol and an excess of ethereal hydrogenchloride was added. The crystalline precipitate was collected andrecrystallized from a mixture of methanol, tetrahydrofuran and ether togive the dihydrochloride as white needles melting at 215-220 (dec.).

(b) Sulfate.A solution of 75.1 g. (0.315 mole) of2-(2-aminoethyl)-l-phenylisoindoline in 325 ml. of ethanol and 25 ml. ofisop'ropyl alcohol was cooled to 18. Aqueous sulfuric acid prepared from17 ml. of concentrated sulfuric acid and ml. of water was brought to 18and added to the cooled solution of 2-(2-aminoethyl)-l-phenylisoindoline. The temperature was maintained at 15, 200 ml. ofisopropyl alcohol was added and the crystalline precipitate wascollected after 30 minutes and washed with three ml. portions ofisopropyl alcohol. The crystalline precipitate was dissolved in 275 ml.of water and filtered, 1000 ml. of isopropyl alcohol was added and afterstanding for 1% hours the crystalline material was collected. Thisprocedurewas repeated using 275 ml. of water and 1000 ml. ofisopropanol. A third recrystallization using 240 ml. of water and 1000ml. of isopropyl alcohol gave white needles which were dried at oversilica gel for 16 hours to give crystals melting at 159163 (dec.).

(c) Maleate.--To a solution of 23.8 g. (0.1 mole) of2-(2-aminoethyl)-1-phenylisoindoline in 50 ml. of ethanol was added 11.6g. (0.1 mole) of maleic acid in 25 ml. of methanol. Ether was added andthe crystalline precipitate was collected. Recrystallizing four timesfrom mixtures of methanol and ether gave white prisms melting at 188-191(dec.).

(d) Cyclohexylsulfamate.-To a solution of 3.4 g. (0.015 mole) of2-(2-aminoethyl)-1-phenylisoindoline in 5 ml. of ethanol and 20 ml. ofchloroform there was added a solution of 2.6 g. (0.014 mole) ofcyclohexylsulfamic acid in 10 ml. of methanol. Ether was added and thecrystalline precipitate was collected. Two recrys- Cir Cal

6. tallizations from mixtures of methanol, chloroform and ether gavewhite prisms melting at 136-141" (dec.).

EXAMPLE 3 Resolution of enantiomers (a) 2-(2-aminoethyl) 1phenylisoindoline.-A solution of 12.5 g. (0.035 mole) of dibenzoyl-D-tartaric acid ([a] =l03.9 [methanol]) in 15 ml. of methanol was added toa solution of 8.3 g. (0.035 mole) of2-(2-aminoethyl)-l-phenylisoindoline in 10 ml. of methanol. On additionof 150 ml. of ethyl acetate and 25 ml. of ether a crystallineprecipitate formed which was collected and washed with chloroform.Recrystallization from a mixture of methanol and ethyl acetate gave 6 g.

" of a material with [a] =20.5 (in methanol). Six

recrystallizations from mixtures of methanol, ethyl acetate and ethergave 2.4 g. of white prisms melting at 167l7l (dec.). [u] =7.3(methanol). The base was freed with aqueous sodium hydroxide, extractedwith ether and distilled in a bulb tube at 0.1 mm. (bath temperature115). A colorless oil was obtained which crystallized to give whiteprisms melting at 68-71 [oz] =+l89.5 (ethanol).

(b) 2-(2-aminoethyl) 1 phenylisoindoline.-To a solution of 17.4 g.(0.073 mole) of 2-(2-aminoethyl)-1- phenylisoindoline in 20 ml. ofmethanol there was added a solution of 26.2 g. (0.073 mole) ofdibenzoyl-D- tartaric acid in 30 ml. of methanol. Addition of 300 ml. ofethyl acetate and 50 ml. of ether produced 24.5 g. of a crystallineprecipitate which was collected. The filtrate was concentrated in vacuo,dissolved in aqueous sodium hydroxide and extracted with ether. Theether layer was dried and concentrated to give a brown oil, which wasdissolved in 250 ml. of ethyl acetate. To this solution was added asolution of 13 g. (0.0353 mole) of dibenzoyl-L-tartaric acid ([oc]=;|-llO.3 [methanol]) in 20 ml. of methanol. Addition of ether gave acrystalline precipitate which was collected. Six recrystallizations frommixtures of methanol, ethyl acetate and ether gave batches with thefollowing rotations: [u] =+24.5, +182", j+8.7, +7.6", +6.9 (inmethanol). A last recrystallization from a mixture of methanol and ethylacetate gave white prisms melting at 162167 (dec.), [a] =6.7 (inmethanol). The base was freed with aqueous sodium hydroxide, extractedwith ether and distilled at 0.1 mm. and -125 (bath temperature). Acolorless oil was obtained which crystallized on scratching to givewhite prisms melting at 68-71" [a] l87.1 (in ethanol).

EXAMPLE 4 Preparation of 2-(3-aminopropyl)-l-phenylisoindolinehydrochloride A solution of 10.7 g. of 2-hydroxymethylbenzhydrol in 35ml. of thionyl chloride was heated on a steam bath for 45 minutes. Theexcess of thionyl chloride was re moved in vacuo to give 11.3 g. of ayellow oil. A solution of 6.3 g. of this crude product in 55 ml. ofbenzene was added to 20 ml. of 1,3-diaminopropane, kept at 25 for 17hours and heated on a steam bath for 2 hours. The mixture wasconcentrated in vacuo and the residue was partitioned in ether and 2 Naqueous sodium hydroxide. The ether phase was dried and concentrated.The residue was distilled at 0.1 mm. and -160 (bath temperature) to givea colorless oil which was dissolved in ether. Addition of etherealhydrogen chloride gave a crystalline precipitate which onrecrystallization from a mixture of ethanol and ether gave white prismsmelting at 211-213".

EXAMPLE 5 Preparation of 2-(2-aminoethyl)-6-chloro-lphenylisoindolinehydrochloride A solution of 9 g. of 3-chloro-6-(hydroxymethyl)benzhydrolin 30 ml. of thionyl chloride was heated on a steam bath for 1 hour andkept at 25 for 1 hour. The excess of thionyl chloride was removed invacuo and the residue was dissolved in 75 ml. of benzene. This solutionwas added to 25 ml. of ethylenediamine. The temperature rose to 38. Themixture was stirred at 25 for 2 hours and concentrated in vacuo. Theresidue was dissolved in ether, washed with water, dried andconcentrated. Distillation at 0.3 mm. and 150 (bath temperature) gave ayellow oil which was dissolved in methylene chloride. Addition ofethanolic hydrogen chloride and ether gave a white precipitate which onrecrystallization from a mixture of methylene chloride and ether gavewhite needles melting at 166-174.

EXAMPLE 6 Preparation of 2-(2-aminoethyl -1- (p-methoxyphenylisoindoline maleate A solution of 10.6 g. of2-hydroxymethyl-4'-methoxybenzhydrol in 35 ml. of thionyl chloride wasrefluxed for 40 minutes and kept at 25 for 1 hour. The excess of thionylchloride was removed in vacuo, the residue was dissolved in benzene andadded to 30 ml. of ethylenediamine. The temperature rose to 35, themixture was cooled to 25 kept at that temperature for 1 hour andconcentrated in vacuo. The residue was dissolved in ether, washed withwater, and extracted with dilute hydrochloric acid. The aqueous phasewas made alkaline, extracted with ether and distilled at 0.25 mm. and150- 155 bath temperature to give a yellow oil. This product wasdissolved in methanol and a methanolic solution of maleic acid wasadded. Addition of ether gave a precipitate which afterrecrystallization from a mixture of methanol and ether gave whiteneedles melting at 164- 165 (dec.).

EXAMPLE 7 Preparation of 2- [4- aminomethyl cyclohexylmethyl]l-phenylisoindoline A solution of 17 g. of crude 2 brommethylbenzhydrylbromide in 68 ml. of benzene was added to 71 ml. of1,4-bis-(aminomethyl)cyclohexane. The temperature rose to 65. Afterstanding at 25 the mixture was diluted with 200 ml. of benzene andwashed with water. The benzene solution was dried and concentrated togive a crystalline residue which was washed with boiling petroleum etherand collected. The product was dissolved in 100 ml. of hot ethanol, andfiltered from the insoluble part. The filtrate was concentrated and theresidue was recrystallized from ether to give 4.2 g. of white prismsmelting at 135137.

EXAMPLE 8 Preparation of 2-(4-aminobutyl)-1-phenylisoindoline A solutionof 19.6 g. of crude 2-bromomethylbenzhydryl bromide in 100 ml. ofbenzene was poured into 44 ml. of 1,4-diaminobutane. The temperaturerose to 62. The mixture was diluted with 50 ml. of benzene and 'kept at25 for 17 hours. Another 50 ml. of benzene was added and the solutionwas washed with water, dried and concentrated. The oily residue wasdissolved in 25 ml. of methanol and a solution of 5.25 g. of maleic acidin 40 ml. of methanol was added. On addition of 50 ml. of ether aprecipitate was obtained which was collected after 1 hour.Recrystallization from a mixture of methanol and ether gave 9.9 g. oflight green prisms melting at 156-159. The base was freed with aqueoussodium hydroxide, extracted with methylene chloride which wasconcentrated. Distillation at 0.2 mm. and 140l60 (bath temperature) gavea colorless oil which crystallized on scratching to give the productmelting at 3237.

8 EXAMPLE 9 Preparation of 2-(2-amino-2-methylpropyl) -1-phenylisoindoline dihydrochloride A solution of 17 g. of crude2-bromomethylbenzhydryl bromide in ml. of benzene was added to 44 ml. of1,2- diamino-Z-methylpropane. The temperature rose to 45. The mixturewas kept at 25 for 17 hours, diluted with benzene and washed with waterand concentrated in vacuo. The residual oil was dissolved in 40 ml. ofethanol and an ethereal solution of hydrogen chloride was added. Aprecipitate was collected and washed with ether. Recrystallizations frommixtures of methanol and ether gave white prisms melting at 230243(dec.).

EXAMPLE '10 Preparation of 2-(2-aminopropyl) -1-phenylis0indolinemaleate A solution of 17 g. of crude 2-bromomethylbenzhydryl bromide in85 ml. of benzene was added to 40 ml. of 1,2-diaminopropane. Thetemperature of the solution rose to 60. The mixture was kept at 25 for 1hour, diluted with ml. of benzene and washed with water, dried andconcentrated in vacuo. The residual oil was dissolved in ether and thebase was extracted with 2 N aqueous hydrochloric acid. The acidic phasewas basified and extracted with ether. This extract gave a yellow oilwhich was dissolved in 20 ml. of methylene chloride. A solution of 4.3g. of maleic acid in 5 ml. of ethanol was added and on addition of ethera crystalline precipitate was formed. Recrystallization from a mixtureof methanol and ether gave White prisms melting at 196199 (dec.).

EXAMPLE 11 Preparation of 2-(2-aminoethyl)-l-(p-hydroxyphenyl) visoindoline dihydrobromide The base was freed from 1 g. of2(2-aminoethyl)-1- (p-methoxyphenyl)isoindoline maleate with aqueoussodium hydroxide. Extraction with ether gave a colorless oil which wasdissolved in 5 ml. of 48 percent aqueous hydrobromic acid and heated to100 for 17 hours. The mixture was cooled and the precipitate wascollected and washed with a mixture of ethanol and ether.Recrystallization from mixtures of methanol and ether gave white prismsmelting at 267-272 (dec.).

The base, 2-(2-aminoethyl) -1- (p-hydroxyphenyl) isoindoline, wasobtained from the dihydrobromide with aqueous ammonia. Recrystallizationfrom a mixture of methylene chloride and petroleum ether gave whiteprisms melting at 178-182 (dec.).

EXAMPLE 12 Preparation of exemplary 2-hydroxymethylbenzhydrolintermediate (a) 2 hydroxymethylbenzhydrol.A suspension of 44.5 g. (1.17mole) of lithium aluminum hydride in 1000 ml. of tetrahydrofuran wasstirred in an ice bath. Small portions of a total of 160.4 g. (0.71mole) of o-benzoylbenzoic acid were added in the course of 30 minutes.The mixture was stirred at 25 for 1 hour. The flask was cooled and 1700ml. of ether followed by 160 ml. of water was added slowly. The mixturewas stirred at 25 for 30 minutes and filtered through a pad of Hy-fio.The clear filtrate was concentrated to an oil which crystallized onscratching.

(b) 3-chloro 6 (hydroxymethyl)benzhydrol.-A solution of 75 g. (0.29mole) of 2 benzoyl 4 chlorobenzoic acid in ml. of thionyl chloride wasrefluxed on a steam bath for 1 hour. The solution was concentrated invacuo and a mixture of 75 ml. of pyridine and ml. of methanol was addedslowly to the cooled residue. The solution was kept at 25 for 17 hours,diluted with 500 ml. of benzene and washed with water. The benzene layerwas dried and concentrated to give a crystalline residue which afterrecrystallization from a mixture of ether and petroleum ether gave whiteprisms of 5-chloro 3 methoxy 3 phenylphthalide melting at 72-74".

A solution of 23 g. (0.094 mole) of 5 chloro-3- methoxy 3phenylphthalide, prepared as above, in 250 ml. of ether was addeddropwise in the course of 45 minutes to a refluxing suspension of 4.75g. (0.125 mole) of lithium aluminum hydride in 350 ml. of ether. Themixture was refluxed for 17 hours, cooled and 25 ml. of water was addedslowly. Filtration gave a clear solution which after evaporation of thesolvent gave a crystalline residue. Recrystallization from a mixture ofether and petroleum ether gave white prisms of 3-chloro-6-(hydroxymethyl)benzhydrol melting at 106-109".

4' chloro 2 hydroxymethylbenzhydrol.A suspension of 22.3 g. (0.588 mole)of lithium aluminum hydride in 500 ml. of tetrahydrofuran was cooled to25. A solution of 92 g. (0.35 mole) of 2-(4'-chlorobenzoyl)- benzoicacid in 900 ml. of ether was added in the course of 30 minutes. Duringthat time the temperature was maintained at ca. 25 and the stirring wascontinued for 1 /2 hours. To this mixture was added 400 ml. of ether,then 88 ml. of water in small portions. After stirring for 30 minutesthe mixture was filtered and the filtrate was concentrated. The residualoil crystallized on scratching and after recrystallization from amixture of ether and petroleum ether gave white prisms of 4-chloro-2-hydroxymethylbenzhydrol melting at 70-74".

EXAMPLE 13 Preparation of 2-(3-hydroxypropyl)-1-phenylisoindoline To asolution of 17 g. of crude 2-bromomethylbenzhydryl bromide in 150 ml. ofbenzene, there was added a solution of 86 ml. of 3-amino 1 propanol in125 ml. of benzene and 50 ml. of ethyl acetate in the course of 2minutes. The temperature was kept at 25 by outside cooling. The mixturewas poured into ice water and extracted with benzene. The extract waswashed with water. dried and concentrated in vacuo. The remaining oilgave white needles which on recrystallization from a mixture ofmethylene chloride and heptane melted at 82-84".

EXAMPLE 14 Preparation of 2-( 2-hydroxyethy1) -1-phenylisoindoline To asolution of 17 g. of crude 2-bromomethylbenzhydryl bromide in 85 ml. ofchloroform, there was added a solution of 30 ml. of ethanolamine in 50ml. of chloroform during the course of 15 minutes. The temperature roseto 53". After the mixture was stirred at 25 for 16 hours, it was dilutedwith water. The chloroform layer was separated, dried and concentrated.A yellow oil was obtained which was dissolved in 50 ml. of ethanol. Thissolution was poured into a solution of 4.5 g. of oxalic acid in 25 ml.of methanol. On addition of ether there were obtained crystals whichafter recrystallization from a mixture of methanol and ether melted at123-126".

EXAMPLE 15 Preparation of 2- 3 -bromopropyl)-1-phenylisoindoline fromo-bromobenzhydryl bromide 3-bromopropylamine was obtained from anaqueous basic solution of 2.4 g. of its hydrobromide by extraction withchloroform. This solution was dried and added to a solution of 3.4 g. of2 bromomethylbenzhydryl bromide in ml. of benzene. Triethylamine (2.8ml.) was added and the solution was kept at 25 for 16 hours. The clearsolution was washed with water and dried. Concentration in vacuo gave anoil which crystallized on scratching. Recrystallization from a mixtureof ethanol and water gave white needles melting at 66-67.

10 EXAMPLE 16 Preparation of 2-(3-bromopropyl)-1-phenylisoindoline from2-(3-hydroxypropyl) -l-phenylisoindoline A solution of 2.5 g. of 2 (3hydroxypropyl)-1- phenylisoindoline in 30 ml. of 48 percent aqueoushydrobromic acid was refluxed for 16 hours, cooled and poured into icecold sodium hydroxide. Extraction with methylene chloride gave a yellowoil which crystallized on standing. Recrystallization from ethanol gavewhite needles melting at 66-67".

EXAMPLE 17 Preparation of 2-(3-aminopropyl)-1-phenylisoindoline from 2-(3-bromopropyl) -1-p|henylisoindoline EXAMPLE 18 This exampleillustrates typical pharmaceutical formulations embodying the novel2-(2-aminoalkyl)-l-phenylisoindoline derivatives of this invention.

TABLET FORMULATION Per tablet, mg.

2-(Z-aminoethyl)-1-phenylisoindoline 10.0 Lactose 129.0 Corn starch 50.0Pregelatinized corn starch 8.0 Calcium stearate 3.0

Total weight 200.0

Procedure (1) Z-(Z-aminoethyl) 1 phenylisoindoline, lactose, corn starchand pregelatinized corn starch were mixed in a suitable mixer.

(2) The mix Was passed through a Fitzpatrick Comminuting Machine fittedwith No. 1A screen and with knives forward.

(3) The mixture was returned to the mixer and moistened with water to athick paste. The moist mass was passed through a No. 12 screen, and themoist granules were dried on paper-lined trays at F.

(4) The dried granules were returned to the mixer, and the calciumstearate was added and mixed well.

(5) The granules were compressed at a tablet weight of 200 mg. usingstandard concave punches having a diameter of yfi inch.

CAPSULE FORMULATION Per capsule, mg.

2-(2-aminoethyl)-l-phenylisoindoline. 25.5 lactose 159.5 Corn starch30.0 Talc 5.0

Total net weight 220.0

Procedure 1 1 machine. (Any similar type capsulating machine may beused.)

PARENTERAL FORMULATION This drug was prepared in duplex ampules, onecontaining the dry drug and the other containing the special diluent.

Dry fill ampul cc., mg. 2.-(2-aminoethyl)-1-phenylisoindoline 20* Aparenteral grade of the drug, fiber-free, was filled into the ampulusing a Diehl Mater electric filler or other suitable type filler. Theampuls were sealed and sterilized at 255 F. for 2. hours.

Immediately before use the powder was solubilized with the followingsolution.

1 Special diluent 2 cc. per ml., mg. Glacial acetic acid 16 Sodiumhydroxide, q.s. to pH 3.0 Water for injection, q.s. to 1.0 ml.

In a suitable container under an atmosphere of nitrogen, the glacialacetic acid was dissolved in part of the water for injection. Sulficientsodium hydroxide was then added to adjust the pH to approximately 3.0.The solution was made to volume, filtered through an 02 Selas candlefilter and filled into 2 cc. flint ampuls. The filling should be doneunder an atmosphere of nitrogen. The ampuls were sealed and sterilizedat 212 F. for 30 minutes. The ampuls were then inspected, and those thatleaked or contained fibers were discarded.

SUPPOSITORY FORMULATION Per 1.3 gm. suppository, gm.

2-(Z-aminoethyl)-1-phenylisoindoline 0.025 Wecobee M 1.230 Carnauba wax0.045

1 E. F. Drew Company, 522 5th Avenue, New York 10, N.Y.

Procedure 1) The Wecobee M and the carnauba wax were melted in asuitable size glass-lined container, mixed well and cooled to 45 C.

(2) 2-(2-aminoethyl)-1-phenylisoindoline, which had been reduced to afine powder with no lumps, was stirred until completely and uniformlydispersed.

(3) The mixture was poured into suppository molds to yield suppositorieshaving an individual weight of 1.3 gms.

(4) The suppositories were cooled and removed from molds. They were thenindividually wrapped in Wax paper for packaging.

We claim: 1. A compound of the formula R 31H B NANHz C I h wherein B iso-phenylene or o-phenylene in which 1 to 4 of the hydrogen atoms havebeen replaced by a member independently selected from the groupconsisting of halogen, lower alkyl, lower alkoxy, hydroxy, amino andtrifluoromethyl; A represents alkylene of 2 to 12 carbon atoms oralkylene of 2 to 12 carbon atoms in which part or all of the carbonatoms are in the form of a carbocycle of 3 to 7 carbon atoms; R ishydrogen or lower alkyl; and Ph represents phenyl or phenyl having 1 to5 substituents independently selected from the group consisting ofhalogen, lower alkyl, lower alkoxy, hydroxy, amino and trifluoromethyland pharmaceutically acceptable acid addition salts thereof.

2. A compound according to claim 1 wherein B is o-phenylene or amono-substituted o-phenylene group 12 and Ph represents phenyl or amono-substituted phenyl group, i.e., a compound of the formula:

wherein A represents alkylene of 2 to 12 carbon atoms or alkylene of 2to 12 carbon atoms in which part or all of the carbon atoms are in theform of a carbocycle of 3 to 7 carbon atoms; R is hydrogen or loweralkyl; and \R and R are each independently selected from the groupconsisting of hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy,amino and trifluoromethyl.

3. The compound according to claim 2 wherein A is cyclohexyldimethyleneand R, R and R are each hydrogen, i.e., the compound 2[4-(aminomethyl)cyclo- 5 hexylmethyl]-1-phenylisoindoline.

4. The compound according to claim 2 wherein A is butylene and R, R andR are each hydrogen, i.e., the compound2-(4-aminobutyl)-1-phenylisoindoline.

5. The compound according to claim 2 wherein A is 2- 0 methylpropyleneand R, R and R are each hydrogen,

i.e., the compound 2-(2 amino 2 methylpropyl)-1- phenylisoindoline.

6. A compound according to claim 2 wherein A represents an alkylenechain of 2 to 3 carbon atoms, i.e., a

- compound of the formula:

wherein R is hydrogen or lower alkyl; R and R are each independentlyselected from the grorp consisting of hydrogen, halogen, lower alkyl,lower alkoxy, hydroxy, amino and trifluoromethyl; and n is an. integerfrom 2 to 4 and pharmaceutically acceptable acid addition salts thereof.

7. The compound according to claim 6 wherein n is 3 and R, R and R areeach hydrogen, i.e., the compound 2-(3-aminopropyl)-1-phenylisoindoline.

8. The compound according to claim 6 wherein n is 3 and R, R and R areeach hydrogen, i.e., the compound 2- (3 -aminopropyl)-1-phenylisoindoline.

9. A compound according to claim 2 wherein n is 2 wherein R and R areeach independently selected from the group consisting of hydrogen,halogen, lower alkyl, lower alkoxy, hydroxy, amino and trifluoromethyl.

10. The compound according to claim 9 wherein (R2 and R are eachhydrogen, i.e., the compound 2-(2-aminoethyl)-l-phenylisoindoline.

11. The dextrorotatory enantiomer of the compound of claim 9, i.e.,(+)-2-(2-aminoethyl) 1 phenylisoindoline.

12. The levorotatory enantiomer of the compound of claim 9, i.e.,(-)-2-(2-aminoethyl)-1-phenylisoindoline.

13. The compound according to claim 9 wherein R is chloro and is in6-position and R is hydrogen, i.e, the compound (2 (2aminoethyl)-6-chloro-1-pheny1- isoindoline.

14; The compound according to claim 9 wherein R is methoxy and is in4-position and R is hydrogen, i.e., the compound 2-(2-aminoethyl)1-(4'-methoxyphenyl) isoindoline.

15. The compound according to claim 9 wherein R is hydroxy and is in4'-position and R is hydrogen, i.e., the compound 2(2-aminoethyl)-1-(4'-hydroxyphenyl) isoindoline.

16. A compound of the formula:

wherein B is o-phenylene or o-phenylene in which 1 to 4 of the hydrogenatoms have been replaced by a member independently selected from thegroup consisting of halogen, lower alkyl, lower alkoxy, hydroxy, amino,and trifluoromethyl; A represents alkylene of 2 to 12 carbon atoms oralkylene of 2 to 12 carbon atoms in which part or all of the carbonatoms are in the form of a carbocycle of 3 to 7 carbon atoms; R ishydrogen or lower alkyl; and Ph represents phenyl or phenyl having 1 tosubstituents independently selected from the group consisting ofhalogen, lower alkyl, lower alkoxy, hydroxy, amino and trifluoromethyl.

17. A compound according to claim 16 wherein A is ethylene or propylene,i.e., a compound of the formula:

N-(CHzh-OH wherein R is hydrogen or lower alkyl; R and R are eachindependently selected from the group consisting of hydrogen, halogen,lower alkyl, lower alkoxy, hydroxy, amino and trifiuoromethyl; and n isan integer from 2 to 4.

18. The compound according to claim 17 wherein n is 2 and R, R and R areeach hydrogen, i.e., the compound2-(2-hydroxyethyl)-l-phenylisoindoline.

19. The compound according to claim 17 wherein n is 3 and R, R and R areeach hydrogen, i.e., the compound2-(3-hydroxypropyl)-1-phenylisoindoline.

20. A compound of the formula:

wherein B is o-phenylene or o-phenylene in which 1 to 4 of the hydrogenatoms have been replaced by a member independently selected from thegroup consisting of halogen, lower alkyl, lower alkoxy, hydroxy, aminoand trifluoromethyl; A represents alkylene of 2 to 12 carbon atoms oralkylene of 2 to 12 carbon atoms in which part or all of the carbonatoms are in the form of a carbocycle of 3 to 7 carbon atoms; R ishydrogen or lower alkyl; Ph represents phenyl or phenyl having 1 to 5substituents independently selected from the group consisting ofhalogen, lower alkyl, lower alkoxy, hydroxy, amino and trifluoromethyl;and X is halogen.

21. A compound according to claim 20 wherein A is ethylene or propylene,i.e., a compound of the formula:

wherein R is hydrogen or lower alkyl; R and R are each independentlyselected from the group consisting of hydrogen, halogen, lower alkyl,lower alkoxy, hydroxy, amino and trifluoromethyl; n is an integer from 2to 4; and X is halogen.

22. A compound of the formula I Ph wherein B is o-phenylene oro-phenylene in which 1 to 4 of the hydrogen atoms have been replaced bya member independently selected from the group consisting of halogen,lower alkyl, lower alkoxy, hydroxy, amino and trifluoromethyl; Phrepresents phenyl or phenyl having 1 to 5 substituents independentlyselected from the group consisting of halogen, lower alkyl, loweralkoxy, hydroxyl r, amino and trifluoromethyl; and n is an integer from2 to 24. A compound of the formula:

wherein n is an integer from 2 to 4.

25. A compound of the formula and pharmaceutically acceptable acidaddition salts thereof.

26. A compound of the formula:

gin-(anemia wherein R is selected from the group consisting of phenyl,monohalophenyl, dihalophenyl, mono (lower)alkylphenyl,di(lower)alkylphenyl, v trifluoromethylphenyl, mono(lower)alkoxyphenyland di(lower)alkoxyphenyl; R is selected from the group consisting ofhydrogen, amino, halogen, lower alkyl and lower alkoxy; R is hydrogenwhen R and R are dissimilar and when R and R are the same they are bothselected from the group consisting of hydrogen, halogen, lower alkyl andlower alkoxy; n is an integer from 2 to 7;

and the pharmaceutically acceptable acid addition salts thereof.

References Cited UNITED STATES PATENTS 4/1962 Huebner 260326.1

1/1963 Hofmann et a1. 16765 US. Cl. X.R.

mg UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,559 Dated January 26, 1971 Inventor(s) Werner Metlesics and Leo HenrykSternbach It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

.- Column 12, line 40, claim 6 "N-(CH) -NH" should be Column 12, line58, claim 8 2-(3-aminopropyl)-" should be 2-(2-aminopropyl) Column 15,lines 11 and 12, claim 25 mono( lowerflalkoxyphenyl" should be mono(lowerha lkoxyphen l Column 16, line 14, insert 27. The compoundaccording to claim 21 wherein n is 5; X is bromo; and R, R and R areeach hydroge i .e. the compound 2-(3-bromopropyl) -lphenylisoindo2 Inthe heading to the printed specification, line 1O, "26 Claims" shouldread 27 Claims Signed and sealed this 21st day of September 1971.

(SEAL) Attest:

EDWARD M.F'LETCHER, JR. ROBERT GOTTSCHALK Attesting Offic ActingCommissioner of Pat

